In a case of recurrence in metastatic breast cancer where the patient was initially hormone receptor-positive, are PIK3CA and ESR1 mutations the only markers that need to be tested to confirm hormone sensitivity in a patient with no detected PIK3CA or ESR1 mutations upon re-biopsy?

PIK3CA and ESR1 Mutations Are NOT the Only Markers for Hormone Sensitivity

No, PIK3CA and ESR1 mutations do not determine hormone sensitivity—you must re-test the actual hormone receptors (ER/PR) and HER2 status on the recurrent/metastatic tissue to confirm hormone sensitivity. 1

Understanding the Distinction

What Determines Hormone Sensitivity

• Hormone receptor status (ER/PR expression by immunohistochemistry) is what defines hormone sensitivity, not PIK3CA or ESR1 mutations 1
• Re-biopsy of metastatic sites should include ER, PR, and HER2 testing because receptor status can change between primary and metastatic disease 1
• Discordance rates between primary and metastatic tumors range from 3.4% to 60% for ER status, making re-testing critical 1

What PIK3CA and ESR1 Mutations Actually Tell You

• PIK3CA mutations guide treatment selection (alpelisib eligibility) in already confirmed HR-positive disease, but do not define hormone sensitivity 1
• ESR1 mutations indicate endocrine resistance mechanisms and may guide choice between aromatase inhibitors versus fulvestrant, but again do not determine if the tumor is hormone-sensitive 1

The Correct Testing Algorithm for Recurrent Disease

Step 1: Confirm Hormone Receptor Status

• Always re-test ER, PR, and HER2 on metastatic tissue when feasible 1
• This is the only way to confirm the tumor remains hormone-sensitive
• Testing should be performed on the most recent tumor sample available 1

Step 2: Test for Actionable Mutations (If HR-Positive Confirmed)

• PIK3CA testing is indicated if the tumor is confirmed HR-positive/HER2-negative to determine alpelisib eligibility 1
  • Use plasma ctDNA first, followed by tissue testing if negative (reflex approach) 1
  • Only 11 specific mutations in exons 7,9, and 20 predict alpelisib benefit 1
• ESR1 mutation testing is NOT routinely recommended per ASCO guidelines, as there is insufficient evidence for clinical utility 1
  • May inform choice between aromatase inhibitors and fulvestrant, but not standard practice 1

Step 3: Consider Additional Biomarkers

• Germline BRCA1/2 testing should be performed if considering PARP inhibitor therapy 1
• This is separate from hormone sensitivity determination but critical for treatment planning

Common Pitfalls to Avoid

Pitfall 1: Assuming Mutations Define Hormone Sensitivity

• PIK3CA and ESR1 are resistance mechanisms, not sensitivity markers 2, 3
• A tumor can be ER-positive (hormone-sensitive) with or without these mutations
• Conversely, these mutations don't make an ER-negative tumor hormone-sensitive

Pitfall 2: Relying on Primary Tumor Results

• Up to 31% of tumors change ER status from positive to negative between primary and metastatic sites 1
• False-negative results on re-biopsy can occur, so clinical judgment remains important 1
• If clinical characteristics suggest hormone sensitivity (long disease-free interval, indolent disease), endocrine therapy may still be reasonable despite negative re-testing 1

Pitfall 3: Testing Plasma Only for PIK3CA

• Only 56% concordance exists between plasma and tissue PIK3CA testing 1
• Always reflex to tissue testing if plasma is negative to avoid missing treatment opportunities 1

Clinical Decision Framework

For your specific case:

1. The absence of PIK3CA or ESR1 mutations tells you nothing about hormone sensitivity
2. You need the ER/PR/HER2 results from the re-biopsy to determine if the tumor remains hormone receptor-positive
3. If ER/PR remain positive, the patient is still hormone-sensitive and eligible for endocrine therapy
4. The absence of PIK3CA mutation means alpelisib is not an option, but standard endocrine therapy ± CDK4/6 inhibitors remains appropriate 1
5. The absence of ESR1 mutation has limited clinical utility per current guidelines 1